The present invention relates to the use of selected compounds to antagonize or inhibit GLP-1 activity in a mammal patient in need thereof, as well as to a pharmaceutical composition comprising such antagonist(s).
Glucagon-like peptide 1(7-36)amide (GLP-1) is an intestinal hormone and neurotransmitter that is involved in the control of metabolism and food intake. A major function of the hormone appears to be the regulation of the amount of insulin released in response to a meal, GLP-1 increasing the insulin secretion. It has therefore been proposed that a molecule capable of augmenting the action of GLP-1, i.e. a GLP-1 agonist, should be useful as an antidiabetic agent to lower elevated blood glucose levels in a mammal serum.
Conversely, a GLP-1 antagonist could be used to elevate the blood glucose level in a subject afflicted with too low a blood glucose level. An exemplary such condition is postprandial reactive hypoglycemia, such as in partially gastrorectomised subjects (Toft-Nielsen M. et al., Diabetologia 41(10):1180-6, 1998). Other disorders where a GLP-1 antagonist is believed to be useful include anorexia (Jensen P. B. et al., J. Clin. Invest. 102(2):503-10, 1998), and reduced intestinal motility and constipation (Tolessa T. et al., Digestive diseases and Sciences 43(10):2284-99, 1998). It has also been suggested that a GLP-1 antagonist could be used to reduce symptoms in Alzheimer""s disease, GLP-1 mediating the inhibition of beta-amyloid induced neural activation (Oka J. I. et al., SO Neuroreport 10(8):1643-6, 1999).
According to the present invention, a limited class of chemical compounds have been found which are excellent antagonists of GLP-1 and therefore would be useful for the treatment of diseases or disorders where inhibition of GLP-1 action would be indicated.
Therefore, in one aspect thereof, the present invention provides a method of antagonizing (e.g., inhibiting) GLP-1 activity in a mammalian patient, comprising administering to said patient an effective amount of a compound of the general formula I: 
wherein:
R1 and R2 independently of each other are C1-4alkyl,
R3 is halogen, hydroxy, C1-4-alkoxy or trifluoromethoxy, and
R4 is hydrogen, hydroxy or C1-4-alkoxy,
or a pharmacologically acceptable salt thereof.
In another aspect, the present invention provides a compound of formula I above for use as a pharmaceutical.
In still another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I above and optionally a pharmaceutically acceptable carrier.
Yet another aspect of the present invention provides the use of a compound of formula I above for the preparation of a medicament for antagonizing GLP-1 activity in a mammalian patient.
This invention also features a method of treating a disorder where inhibition of GLP-1 activity is indicated. The method includes administering to a mammal subject in need thereof an effective amount of a compound of formula I above.
Further, this invention features a method of treating a disorder where inhibition of GLP-1 activity is indicated. The method includes administering to a mammal subject in need thereof a pharmaceutical composition, wherein the pharmaceutical composition includes an effective amount of a compound of formula I above and a pharmaceutically acceptable carrier.
Also within the scope of this invention is a method for the manufacture of a medicament for antagonizing GLP-1 activity in a mammalian patient, characterized in that a compound of formula I above is used as the pharmaceutically active substance.